1. Field of the Invention
This invention relates to novel peptide-substituted heterocyclic compounds useful as immunostimulant and antiinfective agents; to pharmaceutically acceptable salts thereof; to intermediates therefor and to processes for their preparation.
2. Description of the Prior Art
The relatively new field of immunopharmacology, and particularly that segment thereof which deals with immunomodulation, continues to develop at a rapid pace. A variety of naturally occurring compounds has been investigated, including the tetrapeptide tuftsin, known chemically as N.sup.2 -[1-(N.sup.2 -L-threonyl-L-lysyl)-L-prolyl]-L-arginine. Much attention has been directed to synthetic peptidoglycan derivatives, especially those known as muramyl dipeptides. For summaries of the wide range of compounds investigated as immunomodulators, and especially as immunostimulants, attention is directed to Dukar et al., Annu. Rep. Med. Chem., 14, 146-167 (1979), Lederer, J. Med. Chem., 23, 819-825 (1980) and to J. Kralovec, Drugs of the Future, 8, 615-638 (1983).
Immunostimulant peptides have been described in a number of patent specifications:
L-Alanyl-alpha-glutaric acid N-acyl dipeptides in German No. 3,024,355, published Jan. 15, 1981;
tetra- and penta-peptides containing D-alanyl-L-glutamyl moieties or L-alanyl-D-glutamyl moieties in British No. 2,053,231, published Feb. 4, 1981 and German No. 3,024,281, published Jan. 8, 1981, respectively; and
N-acyl-L-alanyl-gamma-D-glutamyl tripeptide derivatives in which the C-terminal amino acid is lysine or diaminopimelic acid in German No. 3,024,369, published Jan. 15, 1981; and
lactyl tetrapeptides composed of N-lactylalanyl, glutamyl, diaminopimelyl and carboxymethylamino components in EP-11283, published May 28, 1980.
Further immunostimulant polypeptides having the formula (A) ##STR3## wherein R.sub.1 is hydrogen or acyl; R.sup.2 is inter alia hydrogen, lower alkyl, hydroxymethyl, benzyl; R.sup.3 and R.sup.4 are each hydrogen, carboxy, --CONR.sup.7 R.sup.8 wherein R.sup.7 is hydrogen, lower alkyl optionally substituted with hydroxy; and R.sup.8 is mono- or dicarboxy lower alkyl; R.sup.5 is hydrogen or carboxy with the proviso that when one of R.sup.4 and R.sup.5 is hydrogen, the other is carboxy or --CONR.sup.7 R.sup.8 ; R.sup.6 is hydrogen; m is 1 to 3 and n is 0 to 2, and derivatives thereof in which the carboxy and amino groups are protected are disclosed in U.S. Pat. Nos. 4,311,640 and 4,322,341; EP applications 25,482; 50,856; 51,812; 53,388; 55,846 and 57,419.
None of the polypeptides disclosed in the art has a heterocyclyl containing amino acid moiety at the position occupied by variable R.sup.4 in the above formula. U.S. application Ser. No. 595,169, filed Mar. 30, 1984 by Ives et al., describes polypeptides wherein variable R.sup.4 is a basic amino acid moiety.
Kitaura et al., J. Med. Chem, 25, 335-337 (1982) report N.sup.2 -(gamma-D-glutamyl)-meso-2(L),2'(D)-diaminopimelic acid as the minimal structure capable of eliciting a biological response characteristic of the compound of formula (A) wherein n is 1; R.sup.1 is CH.sub.3 CH(OH)--CO--; R.sup.2 is CH.sub.3 ; each of R.sup.3 and R.sup.5 is --COOH; R.sup.4 is --CONHCH.sub.2 COOH; and R.sup.6 is H. Said compound of formula (A) is known as FK-156.